Animals such as mammals and birds are often susceptible to endoparasitic and/or ectoparasitic infection and infestation. Ectoparasites include fleas, ticks, mites, lice, mosquitoes and flies, all of which can adversely affect the health of the animal. Endoparasites, those parasites that live within the host animal also adversely affect the health of the infected animal. Helminthiasis, which is most frequently caused by a group of parasitic worms categorized as cestodes (tapeworm), nematodes (roundworm) and trematodes (flatworm or flukes) are all examples of endoparasites.
Anthelmintic and ectoparasitic agents have been effective against parasites, however, resistance to single antiparasitic compounds is becoming common. Combinations of these agents have been introduced as a means for gaining a broader range of parasitic control as well as in defense of the rising rates of resistance.
There are technical challenges for preparing a stable liquid composition comprising a macrocyclic lactone or derivative thereof, with at least one other antiparasitic agent, for example an imidathiazole. WO 2009/070687 discloses a pour-on composition with a macrocyclic lactone and clorsulon with a stability enhancer. The application recites that certain antiparasitic agents degrade without the presence of a stability enhancer, for example, glycerol formal and polyethylene glycol. WO2010/021555 recites a stabilized formulation comprising a macrocyclic lactone, levamisole, or an equivalent agent, and a modified starch as a stabilizer (i.e. hydroxypropyl starch phosphate). WO 2011/143479 discloses a formulation approach for an injectable solution comprising a system of solvents, including at least one surfactant, combined to produce a micellar solution that is relatively stable and suitable for injection. While these references disclose the use of various solvents, surfactants, and stability enhancers, none disclose the use of an amino sugar as a stability enhancer, particularly for use as an oral, topical, and injectable composition.
The combination of a macrocyclic lactone with levamisole, particularly acidic salts of levamisole, presents a number of challenges from a formulation solubility and stability perspective, as levamisole is known to be acid-stable, while the macrocyclic lactones are acid labile and are subject to hydrolytic degradation. Macrocyclic lactones, or derivatives thereof, such as doramectin, selamectin, milbemycin, and moxidectin, are stable at a neutral pH. The present invention describes the use of a stability enhancing amino sugar across a wide range of antiparasitic agent concentrations that can provide an efficacious veterinary dosage form with suitable solubility, stability, and shelf life, thereby allowing for increased antiparasitic efficacy and reduced resistance.